Solid-Phase Synthesis of Azole-Comprising Peptidomimetics and Coordination of a Designed Analog to Zn2+

Peptidomimetics that can coordinate transition metals have a variety of potential applications as catalysts, sensors, or materials. A new modular peptidomimetic scaffold, the “azole peptoid”, is introduced here. We report methods for the solid-phase synthesis of eleven examples of trimeric N-substituted oligoamides that include oxazole- or thiazole-functionalized backbones. The products prepared comprise a diversity of functionality, including a metal-coordinating terpyridine group. The modular synthetic approach enables ready preparation of analogs for specific applications. To highlight a potential use of this new synthetic scaffold, a trimeric azole peptoid functionalized with a terpyridine residue was prepared and studied. The characteristic 2:1 ligand:metal binding of this terpyridine-functionalized azole peptoid to Zn2+ in aqueous solution was observed. These studies introduce azole peptoids as a useful class of biomimetic molecules for further study and application

The human platelet transcriptome and proteome is altered and pro-thrombotic functional responses are increased during prolonged hypoxia exposure at high altitude

Exposure to hypoxia, through ascension to high altitudes (HAs), air travel, or human disease, is associated with an increased incidence of thrombosis in some settings. Mechanisms underpinning this increased thrombosis risk remain incompletely understood, and the effects of more sustained hypoxia on the human platelet molecular signature and associated functional responses have never been examined. We examined the effects of prolonged (≥2 months continuously) hypobaric hypoxia on platelets isolated from subjects residing at HA (3,700 meters) and, for comparison, matched subjects residing under normoxia conditions at sea level (50 meters). Using complementary transcriptomic, proteomic, and functional methods, we identified that the human platelet transcriptome is markedly altered under prolonged exposure to hypobaric hypoxia at HA. Among the significantly, differentially expressed genes (mRNA and protein), were those having canonical roles in platelet activation and thrombosis, including membrane glycoproteins (e.g. GP4, GP6, GP9), integrin subunits (e.g. ITGA2B), and alpha-granule chemokines (e.g. SELP, PF4V1). Platelets from subjects residing at HA were hyperactive, as demonstrated by increased engagement and adhesion to fibrinogen, fewer alpha granules by transmission electron microscopy, increased circulating PF4 and ADP, and significantly enhanced clot retraction. In conclusion, we identify that prolonged hypobaric hypoxia exposure due to HA alters the platelet transcriptome and proteome, triggering increased functional activation responses that may contribute to thrombosis. Our findings may also have relevance across a range of human diseases where chronic hypoxia, platelet activation, and thrombosis are increased

Solution effects on the self‐association of a water‐soluble peptoid

A desire to replicate the structural and functional complexity of proteins with structured, sequence‐specific oligomers motivates study of the structural features of water‐soluble peptoids (N ‐substituted glycine oligomers). Understanding the molecular‐level details of peptoid self‐assembly in water is essential to advance peptoids\u27 application as novel materials. Peptoid 1 , an amphiphilic, putatively helical peptoid previously studied in our laboratory, shows evidence of self‐association in aqueous solution. In this work, we evaluate how changes to aqueous solution conditions influence the self‐association of 1 . We report that changes to pH influence the fluorescence and CD spectroscopic features as well as the peptoid\u27s interaction with a solvatochromic fluorophore and its apparent size as estimated by size exclusion chromatography. Addition of guanidine hydrochloride and ammonium sulfate also modulate spectroscopic features of the peptoid, its interaction with a solvatochromic fluorophore, and its elution in size exclusion chromatography. These data suggest that the ordering of the self‐assembly changes in response to pH and with solvent additives and is more ordered at higher pH and in the presence of guanidine hydrochloride. The deeper understanding of the self‐association of 1 afforded by these studies informs the design of new stimuli‐responsive peptoids with stable tertiary or quaternary structures

Dosimetric Advantage of Combined IMRT for Whole Lung and Abdomen Irradiation for Wilms Tumor

Purpose: In patients with Wilms tumor with lung metastases, a cardiac-sparing intensity modulated radiation therapy (CS-IMRT) technique is increasingly being adopted for whole lung irradiation. However, the standard technique for flank and whole abdomen radiation remains 2-dimensional anterioposterior (AP), and overlap at the junction between the whole lung CS-IMRT and abdominal AP fields can result in overdose to normal organs. Here, we compared the dosimetry of patients who received whole lung irradiation and flank or abdominal radiation therapy with CS-IMRT with AP abdominal field (IMRT-AP) versus CS-IMRT with IMRT abdominal field (combined IMRT). Methods and Materials: We retrospectively reviewed the radiation plans of 2 patients with Wilms tumor who received CS-IMRT and flank or whole abdomen irradiation with a combined IMRT approach. Comparison IMRT-AP plans were generated with equivalent target coverage of 95% receiving the prescribed dose. Maximum doses to normal organs were compared at the junctional overlap. Results: Overlap at the junction between CS-IMRT and abdominal fields resulted in a significantly lower dose with combined IMRT plans compared with IMRT-AP plan. Differences in maximum doses (in cGy) to normal organs between combined IMRT versus IMRT-AP plans were most significant in the vertebral body (patient 1 = 1277 vs 2065; patient 2 = 1334 vs 2287), lungs (patient 1 = 1298 vs 2081; patient 2 = 1234 vs 1820), spinal cord (patient 1 = 1235 vs 1975; patient 2 = 1345 vs 2253), stomach (patient 1 = 1264 vs 1977; patient 2 = 1118 vs 2062), and liver (patient 1 = 1297 vs 1889; patient 2 = 1334 vs 2237). Conclusions: The combined IMRT approach for Wilms patients who require whole lung and abdomen irradiation can provide more uniform dose distribution in the junction area and significantly lower doses to normal organs at the junctional overlap